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1.
Proc Natl Acad Sci U S A ; 121(41): e2413357121, 2024 Oct 08.
Artículo en Inglés | MEDLINE | ID: mdl-39361644

RESUMEN

Metal ions have important roles in supporting the catalytic activity of DNA-regulating enzymes such as topoisomerases (topos). Bacterial type II topos, gyrases and topo IV, are primary drug targets for fluoroquinolones, a class of clinically relevant antibacterials requiring metal ions for efficient drug binding. While the presence of metal ions in topos has been elucidated in biochemical studies, accurate location and assignment of metal ions in structural studies have historically posed significant challenges. Recent advances in X-ray crystallography address these limitations by extending the experimental capabilities into the long-wavelength range, exploiting the anomalous contrast from light elements of biological relevance. This breakthrough enables us to confirm experimentally the locations of Mg2+ in the fluoroquinolone-stabilized Streptococcus pneumoniae topo IV complex. Moreover, we can unambiguously identify the presence of K+ and Cl- ions in the complex with one pair of K+ ions functioning as an additional intersubunit bridge. Overall, our data extend current knowledge on the functional and structural roles of metal ions in type II topos.


Asunto(s)
Magnesio , Streptococcus pneumoniae , Streptococcus pneumoniae/enzimología , Sitios de Unión , Cristalografía por Rayos X , Magnesio/metabolismo , Magnesio/química , Potasio/metabolismo , Potasio/química , Metales/metabolismo , Metales/química , ADN-Topoisomerasas de Tipo II/metabolismo , ADN-Topoisomerasas de Tipo II/química , Fluoroquinolonas/química , Fluoroquinolonas/metabolismo , Iones/metabolismo , Topoisomerasa de ADN IV/metabolismo , Topoisomerasa de ADN IV/química , Modelos Moleculares , Proteínas Bacterianas/metabolismo , Proteínas Bacterianas/química , Proteínas Bacterianas/genética , Cloruros/metabolismo , Cloruros/química
2.
Brain ; 146(11): 4766-4783, 2023 11 02.
Artículo en Inglés | MEDLINE | ID: mdl-37437211

RESUMEN

KPTN-related disorder is an autosomal recessive disorder associated with germline variants in KPTN (previously known as kaptin), a component of the mTOR regulatory complex KICSTOR. To gain further insights into the pathogenesis of KPTN-related disorder, we analysed mouse knockout and human stem cell KPTN loss-of-function models. Kptn -/- mice display many of the key KPTN-related disorder phenotypes, including brain overgrowth, behavioural abnormalities, and cognitive deficits. By assessment of affected individuals, we have identified widespread cognitive deficits (n = 6) and postnatal onset of brain overgrowth (n = 19). By analysing head size data from their parents (n = 24), we have identified a previously unrecognized KPTN dosage-sensitivity, resulting in increased head circumference in heterozygous carriers of pathogenic KPTN variants. Molecular and structural analysis of Kptn-/- mice revealed pathological changes, including differences in brain size, shape and cell numbers primarily due to abnormal postnatal brain development. Both the mouse and differentiated induced pluripotent stem cell models of the disorder display transcriptional and biochemical evidence for altered mTOR pathway signalling, supporting the role of KPTN in regulating mTORC1. By treatment in our KPTN mouse model, we found that the increased mTOR signalling downstream of KPTN is rapamycin sensitive, highlighting possible therapeutic avenues with currently available mTOR inhibitors. These findings place KPTN-related disorder in the broader group of mTORC1-related disorders affecting brain structure, cognitive function and network integrity.


Asunto(s)
Transducción de Señal , Serina-Treonina Quinasas TOR , Humanos , Animales , Ratones , Transducción de Señal/genética , Serina-Treonina Quinasas TOR/metabolismo , Encéfalo/metabolismo , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Cognición , Proteínas de Microfilamentos/genética
3.
Cochrane Database Syst Rev ; 3: CD003316, 2020 03 20.
Artículo en Inglés | MEDLINE | ID: mdl-32196635

RESUMEN

BACKGROUND: Levels of physical activity and physical fitness are low after stroke. Interventions to increase physical fitness could reduce mortality and reduce disability through increased function. OBJECTIVES: The primary objectives of this updated review were to determine whether fitness training after stroke reduces death, death or dependence, and disability. The secondary objectives were to determine the effects of training on adverse events, risk factors, physical fitness, mobility, physical function, health status and quality of life, mood, and cognitive function. SEARCH METHODS: In July 2018 we searched the Cochrane Stroke Trials Register, CENTRAL, MEDLINE, Embase, CINAHL, SPORTDiscus, PsycINFO, and four additional databases. We also searched ongoing trials registers and conference proceedings, screened reference lists, and contacted experts in the field. SELECTION CRITERIA: Randomised trials comparing either cardiorespiratory training or resistance training, or both (mixed training), with usual care, no intervention, or a non-exercise intervention in stroke survivors. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies, assessed quality and risk of bias, and extracted data. We analysed data using random-effects meta-analyses and assessed the quality of the evidence using the GRADE approach. Diverse outcome measures limited the intended analyses. MAIN RESULTS: We included 75 studies, involving 3017 mostly ambulatory participants, which comprised cardiorespiratory (32 studies, 1631 participants), resistance (20 studies, 779 participants), and mixed training interventions (23 studies, 1207 participants). Death was not influenced by any intervention; risk differences were all 0.00 (low-certainty evidence). There were few deaths overall (19/3017 at end of intervention and 19/1469 at end of follow-up). None of the studies assessed death or dependence as a composite outcome. Disability scores were improved at end of intervention by cardiorespiratory training (standardised mean difference (SMD) 0.52, 95% CI 0.19 to 0.84; 8 studies, 462 participants; P = 0.002; moderate-certainty evidence) and mixed training (SMD 0.23, 95% CI 0.03 to 0.42; 9 studies, 604 participants; P = 0.02; low-certainty evidence). There were too few data to assess the effects of resistance training on disability. Secondary outcomes showed multiple benefits for physical fitness (VO2 peak and strength), mobility (walking speed) and physical function (balance). These physical effects tended to be intervention-specific with the evidence mostly low or moderate certainty. Risk factor data were limited or showed no effects apart from cardiorespiratory fitness (VO2 peak), which increased after cardiorespiratory training (mean difference (MD) 3.40 mL/kg/min, 95% CI 2.98 to 3.83; 9 studies, 438 participants; moderate-certainty evidence). There was no evidence of any serious adverse events. Lack of data prevents conclusions about effects of training on mood, quality of life, and cognition. Lack of data also meant benefits at follow-up (i.e. after training had stopped) were unclear but some mobility benefits did persist. Risk of bias varied across studies but imbalanced amounts of exposure in control and intervention groups was a common issue affecting many comparisons. AUTHORS' CONCLUSIONS: Few deaths overall suggest exercise is a safe intervention but means we cannot determine whether exercise reduces mortality or the chance of death or dependency. Cardiorespiratory training and, to a lesser extent mixed training, reduce disability during or after usual stroke care; this could be mediated by improved mobility and balance. There is sufficient evidence to incorporate cardiorespiratory and mixed training, involving walking, within post-stroke rehabilitation programmes to improve fitness, balance and the speed and capacity of walking. The magnitude of VO2 peak increase after cardiorespiratory training has been suggested to reduce risk of stroke hospitalisation by ˜7%. Cognitive function is under-investigated despite being a key outcome of interest for patients. Further well-designed randomised trials are needed to determine the optimal exercise prescription, the range of benefits and any long-term benefits.


Asunto(s)
Terapia por Ejercicio/métodos , Aptitud Física , Rehabilitación de Accidente Cerebrovascular , Caminata/fisiología , Actividades Cotidianas , Humanos , Persona de Mediana Edad , Fuerza Muscular , Consumo de Oxígeno , Rendimiento Físico Funcional , Equilibrio Postural , Ensayos Clínicos Controlados Aleatorios como Asunto , Entrenamiento de Fuerza , Accidente Cerebrovascular/mortalidad , Sobrevivientes , Velocidad al Caminar/fisiología
4.
BMC Health Serv Res ; 20(1): 1066, 2020 Nov 23.
Artículo en Inglés | MEDLINE | ID: mdl-33228683

RESUMEN

BACKGROUND: To identify and rank the importance of key determinants of high medical expenses among breast cancer patients and to understand the underlying effects of these determinants. METHODS: The Oncology Care Model (OCM) developed by the Center for Medicare & Medicaid Innovation were used. The OCM data provided to Mount Sinai on 2938 breast-cancer episodes included both baseline periods and three performance periods between Jan 1, 2012 and Jan 1, 2018. We included 11 variables representing information on treatment, demography and socio-economics status, in addition to episode expenditures. OCM data were collected from participating practices and payers. We applied a principled variable selection algorithm using a flexible tree-based machine learning technique, Quantile Regression Forests. RESULTS: We found that the use of chemotherapy drugs (versus hormonal therapy) and interval of days without chemotherapy predominantly affected medical expenses among high-cost breast cancer patients. The second-tier major determinants were comorbidities and age. Receipt of surgery or radiation, geographically adjusted relative cost and insurance type were also identified as important high-cost drivers. These factors had disproportionally larger effects upon the high-cost patients. CONCLUSIONS: Data-driven machine learning methods provide insights into the underlying web of factors driving up the costs for breast cancer care management. Results from our study may help inform population health management initiatives and allow policymakers to develop tailored interventions to meet the needs of those high-cost patients and to avoid waste of scarce resource.


Asunto(s)
Neoplasias de la Mama , Anciano , Neoplasias de la Mama/terapia , Costos de la Atención en Salud , Gastos en Salud , Humanos , Aprendizaje Automático , Medicare , Estados Unidos
5.
BMC Health Serv Res ; 20(1): 350, 2020 Apr 25.
Artículo en Inglés | MEDLINE | ID: mdl-32334595

RESUMEN

BACKGROUND: The Oncology Care Model (OCM) was developed as a payment model to encourage participating practices to provide better-quality care for cancer patients at a lower cost. The risk-adjustment model used in OCM is a Gamma generalized linear model (Gamma GLM) with log-link. The predicted value of expense for the episodes identified for our academic medical center (AMC), based on the model fitted to the national data, did not correlate well with our observed expense. This motivated us to fit the Gamma GLM to our AMC data and compare it with two other flexible modeling methods: Random Forest (RF) and Partially Linear Additive Quantile Regression (PLAQR). We also performed a simulation study to assess comparative performance of these methods and examined the impact of non-linearity and interaction effects, two understudied aspects in the field of cost prediction. METHODS: The simulation was designed with an outcome of cost generated from four distributions: Gamma, Weibull, Log-normal with a heteroscedastic error term, and heavy-tailed. Simulation parameters both similar to and different from OCM data were considered. The performance metrics considered were the root mean square error (RMSE), mean absolute prediction error (MAPE), and cost accuracy (CA). Bootstrap resampling was utilized to estimate the operating characteristics of the performance metrics, which were described by boxplots. RESULTS: RF attained the best performance with lowest RMSE, MAPE, and highest CA for most of the scenarios. When the models were misspecified, their performance was further differentiated. Model performance differed more for non-exponential than exponential outcome distributions. CONCLUSIONS: RF outperformed Gamma GLM and PLAQR in predicting overall and top decile costs. RF demonstrated improved prediction under various scenarios common in healthcare cost modeling. Additionally, RF did not require prespecification of outcome distribution, nonlinearity effect, or interaction terms. Therefore, RF appears to be the best tool to predict average cost. However, when the goal is to estimate extreme expenses, e.g., high cost episodes, the accuracy gained by RF versus its computational costs may need to be considered.


Asunto(s)
Costos de la Atención en Salud/estadística & datos numéricos , Aprendizaje Automático , Modelos Estadísticos , Simulación por Computador , Humanos , Modelos Lineales , Oncología Médica/economía , Ajuste de Riesgo
6.
Cochrane Database Syst Rev ; 3: CD003316, 2016 Mar 24.
Artículo en Inglés | MEDLINE | ID: mdl-27010219

RESUMEN

BACKGROUND: Levels of physical fitness are low after stroke. It is unknown whether improving physical fitness after stroke reduces disability. OBJECTIVES: To determine whether fitness training after stroke reduces death, dependence, and disability and to assess the effects of training with regard to adverse events, risk factors, physical fitness, mobility, physical function, quality of life, mood, and cognitive function. Interventions to improve cognitive function have attracted increased attention after being identified as the highest rated research priority for life after stroke. Therefore we have added this class of outcomes to this updated review. SEARCH METHODS: We searched the Cochrane Stroke Group Trials Register (last searched February 2015), the Cochrane Central Register of Controlled Trials (CENTRAL 2015, Issue 1: searched February 2015), MEDLINE (1966 to February 2015), EMBASE (1980 to February 2015), CINAHL (1982 to February 2015), SPORTDiscus (1949 to February 2015), and five additional databases (February 2015). We also searched ongoing trials registers, handsearched relevant journals and conference proceedings, screened reference lists, and contacted experts in the field. SELECTION CRITERIA: Randomised trials comparing either cardiorespiratory training or resistance training, or both (mixed training), with usual care, no intervention, or a non-exercise intervention in stroke survivors. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials, assessed quality and risk of bias, and extracted data. We analysed data using random-effects meta-analyses. Diverse outcome measures limited the intended analyses. MAIN RESULTS: We included 58 trials, involving 2797 participants, which comprised cardiorespiratory interventions (28 trials, 1408 participants), resistance interventions (13 trials, 432 participants), and mixed training interventions (17 trials, 957 participants). Thirteen deaths occurred before the end of the intervention and a further nine before the end of follow-up. No dependence data were reported. Diverse outcome measures restricted pooling of data. Global indices of disability show moderate improvement after cardiorespiratory training (standardised mean difference (SMD) 0.52, 95% confidence interval (CI) 0.19 to 0.84; P value = 0.002) and by a small amount after mixed training (SMD 0.26, 95% CI 0.04 to 0.49; P value = 0.02); benefits at follow-up (i.e. after training had stopped) were unclear. There were too few data to assess the effects of resistance training.Cardiorespiratory training involving walking improved maximum walking speed (mean difference (MD) 6.71 metres per minute, 95% CI 2.73 to 10.69), preferred gait speed (MD 4.28 metres per minute, 95% CI 1.71 to 6.84), and walking capacity (MD 30.29 metres in six minutes, 95% CI 16.19 to 44.39) at the end of the intervention. Mixed training, involving walking, increased preferred walking speed (MD 4.54 metres per minute, 95% CI 0.95 to 8.14), and walking capacity (MD 41.60 metres per six minutes, 95% CI 25.25 to 57.95). Balance scores improved slightly after mixed training (SMD 0.27, 95% CI 0.07 to 0.47). Some mobility benefits also persisted at the end of follow-up. The variability, quality of the included trials, and lack of data prevents conclusions about other outcomes and limits generalisability of the observed results. AUTHORS' CONCLUSIONS: Cardiorespiratory training and, to a lesser extent, mixed training reduce disability during or after usual stroke care; this could be mediated by improved mobility and balance. There is sufficient evidence to incorporate cardiorespiratory and mixed training, involving walking, within post-stroke rehabilitation programmes to improve the speed and tolerance of walking; some improvement in balance could also occur. There is insufficient evidence to support the use of resistance training. The effects of training on death and dependence after stroke are still unclear but these outcomes are rarely observed in physical fitness training trials. Cognitive function is under-investigated despite being a key outcome of interest for patients. Further well-designed randomised trials are needed to determine the optimal exercise prescription and identify long-term benefits.


Asunto(s)
Terapia por Ejercicio/métodos , Aptitud Física , Rehabilitación de Accidente Cerebrovascular , Caminata/fisiología , Actividades Cotidianas , Humanos , Ensayos Clínicos Controlados Aleatorios como Asunto , Entrenamiento de Fuerza , Accidente Cerebrovascular/mortalidad
7.
Brain Inj ; 30(7): 864-71, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27058006

RESUMEN

OBJECTIVE: Although white matter hyperintensity (WMH) pathology has been observed in the context of traumatic brain injury (TBI), the contribution of this type of macrostructural damage to cognitive and/or post-concussive symptomatology (PCS) remains unclear. METHODS: Sixty-eight Veterans (mTBI = 46, Military Controls [MCs] = 22) with and without history of mild TBI (mTBI) underwent structural MRI and comprehensive cognitive and psychiatric assessment. WMH volume was identified as deep (DWMH) or periventricular (PVWMH) on fluid-attenuated inversion recovery (FLAIR) images. RESULTS: Group analyses revealed that mTBI history was not associated with increased WMH pathology (p's > 0.05). However, after controlling for post-traumatic stress disorder (PTSD) and intracranial volume, DWMH was associated with reduced short-and long-delayed memory performance within the mTBI group (p's < 0.05). Additionally, after adjusting for PTSD and time since injury, regression analyses revealed that WMH was not associated with self-reported ratings of PCS (p's > 0.05) in the mTBI group. CONCLUSIONS: The results demonstrate that, in relatively young Veterans with mTBI, DWMH differentially and negatively affects memory performance above and beyond the effects of PTSD symptoms. The findings may help to clarify prior mixed results as well as offer focused treatment implications for Veterans with history of neurotrauma and evidence of macrostructural white matter damage.


Asunto(s)
Lesiones Traumáticas del Encéfalo/diagnóstico por imagen , Memoria/fisiología , Trastornos por Estrés Postraumático/diagnóstico por imagen , Veteranos/psicología , Sustancia Blanca/diagnóstico por imagen , Adulto , Lesiones Traumáticas del Encéfalo/complicaciones , Lesiones Traumáticas del Encéfalo/psicología , Cognición/fisiología , Femenino , Humanos , Puntaje de Gravedad del Traumatismo , Imagen por Resonancia Magnética , Masculino , Pruebas Neuropsicológicas , Tamaño de los Órganos , Trastornos por Estrés Postraumático/complicaciones , Trastornos por Estrés Postraumático/psicología , Adulto Joven
9.
Nucleic Acids Res ; 41(21): 9911-23, 2013 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-23965305

RESUMEN

Type II topoisomerases regulate DNA supercoiling and chromosome segregation. They act as ATP-operated clamps that capture a DNA duplex and pass it through a transient DNA break in a second DNA segment via the sequential opening and closure of ATPase-, G-DNA- and C-gates. Here, we present the first 'open clamp' structures of a 3-gate topoisomerase II-DNA complex, the seminal complex engaged in DNA recognition and capture. A high-resolution structure was solved for a (full-length ParE-ParC55)2 dimer of Streptococcus pneumoniae topoisomerase IV bound to two DNA molecules: a closed DNA gate in a B-A-B form double-helical conformation and a second B-form duplex associated with closed C-gate helices at a novel site neighbouring the catalytically important ß-pinwheel DNA-binding domain. The protein N gate is present in an 'arms-wide-open' state with the undimerized N-terminal ParE ATPase domains connected to TOPRIM domains via a flexible joint and folded back allowing ready access both for gate and transported DNA segments and cleavage-stabilizing antibacterial drugs. The structure shows the molecular conformations of all three gates at 3.7 Å, the highest resolution achieved for the full complex to date, and illuminates the mechanism of DNA capture and transport by a type II topoisomerase.


Asunto(s)
Topoisomerasa de ADN IV/química , ADN/química , Adenosina Trifosfatasas/química , Adenosina Trifosfato/química , Sitios de Unión , Transporte Biológico , ADN/metabolismo , Topoisomerasa de ADN IV/metabolismo , Modelos Moleculares , Estructura Terciaria de Proteína , Streptococcus pneumoniae/enzimología
11.
J Intensive Care Soc ; 25(3): 339-345, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-39224422

RESUMEN

Decompressive craniectomy (DC) involves surgical removal of the skull that overlies swollen, imperiled, brain. This is done to combat intracranial hypertension and mitigate a vicious cycle of secondary brain injury. If, instead, this pathophysiology goes uninterrupted, it can mean brain herniation and brain stem death. As such, DC can save lives when all else fails. Regardless, it is no panacea and can also "ruin deaths," and leave patients profoundly disabled. DC is not a new procedure; however, this therapy is increasingly noteworthy due to advances in neurocritical care, alongside ethical concerns. We cover the physiological rationale, the surgical basics, the trial data, and focus on secondary decompression (for refractory intracranial pressure (ICP)) rather than primary decompression (i.e. during evacuation of an intracranial mass). Given that DC should not be undertaken indiscriminately, we conclude by introducing ways in which to discuss DC with families and colleagues. Our goal is to provide a primer and common resource for the multidisciplinary team. We aim to increase not only knowledge but wisdom, prudence, collegiality, and family-focused care.

13.
Cochrane Database Syst Rev ; (10): CD003316, 2013 Oct 21.
Artículo en Inglés | MEDLINE | ID: mdl-24142492

RESUMEN

BACKGROUND: Levels of physical fitness are low after stroke. It is unknown whether improving physical fitness after stroke reduces disability. OBJECTIVES: To determine whether fitness training after stroke reduces death, dependence, and disability. The secondary aims were to determine the effects of training on physical fitness, mobility, physical function, quality of life, mood, and incidence of adverse events. SEARCH METHODS: We searched the Cochrane Stroke Group Trials Register (last searched January 2013), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 12: searched January 2013), MEDLINE (1966 to January 2013), EMBASE (1980 to January 2013), CINAHL (1982 to January 2013), SPORTDiscus (1949 to January 2013), and five additional databases (January 2013). We also searched ongoing trials registers, handsearched relevant journals and conference proceedings, screened reference lists, and contacted experts in the field. SELECTION CRITERIA: Randomised trials comparing either cardiorespiratory training or resistance training, or both, with no intervention, a non-exercise intervention, or usual care in stroke survivors. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials, assessed quality, and extracted data. We analysed data using random-effects meta-analyses. Diverse outcome measures limited the intended analyses. MAIN RESULTS: We included 45 trials, involving 2188 participants, which comprised cardiorespiratory (22 trials, 995 participants), resistance (eight trials, 275 participants), and mixed training interventions (15 trials, 918 participants). Nine deaths occurred before the end of the intervention and a further seven at the end of follow-up. No dependence data were reported. Diverse outcome measures made data pooling difficult. Global indices of disability show a tendency to improve after cardiorespiratory training (standardised mean difference (SMD) 0.37, 95% confidence interval (CI) 0.10 to 0.64; P = 0.007); benefits at follow-up and after mixed training were unclear. There were insufficient data to assess the effects of resistance training.Cardiorespiratory training involving walking improved maximum walking speed (mean difference (MD) 7.37 metres per minute, 95% CI 3.70 to 11.03), preferred gait speed (MD 4.63 metres per minute, 95% CI 1.84 to 7.43), walking capacity (MD 26.99 metres per six minutes, 95% CI 9.13 to 44.84), and Berg Balance scores (MD 3.14, 95% CI 0.56 to 5.73) at the end of the intervention. Mixed training, involving walking, increased preferred walking speed (MD 4.54 metres per minute, 95% CI 0.95 to 8.14), walking capacity (MD 41.60 metres per six minutes, 95% CI 25.25 to 57.95), and also pooled balance scores but the evidence is weaker (SMD 0.26 95% CI 0.04 to, 0.49). Some mobility benefits also persisted at the end of follow-up. The variability and trial quality hampered the assessment of the reliability and generalisability of the observed results. AUTHORS' CONCLUSIONS: The effects of training on death and dependence after stroke are unclear. Cardiorespiratory training reduces disability after stroke and this may be mediated by improved mobility and balance. There is sufficient evidence to incorporate cardiorespiratory and mixed training, involving walking, within post-stroke rehabilitation programs to improve the speed and tolerance of walking; improvement in balance may also occur. There is insufficient evidence to support the use of resistance training. Further well-designed trials are needed to determine the optimal content of the exercise prescription and identify long-term benefits.


Asunto(s)
Terapia por Ejercicio/métodos , Aptitud Física , Rehabilitación de Accidente Cerebrovascular , Caminata/fisiología , Actividades Cotidianas , Humanos , Ensayos Clínicos Controlados Aleatorios como Asunto , Entrenamiento de Fuerza , Accidente Cerebrovascular/mortalidad
14.
Health Serv Insights ; 16: 11786329231163008, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37008409

RESUMEN

Value-based care initiatives require accurate quantification of resource utilization. This study explores hospital resource documentation performance for total knee and hip arthroplasty (TKA, THA) implants and how this may differ between hospitals. This retrospective study utilized the Premier discharge database, years 2006 to 2020. TKA/THA cases were categorized into 5 tiers based upon the completeness of implant component documentation: Platinum, Gold, Silver, Bronze, Poor. Correlation between TKA and THA documentation performance (per-hospital percentage of Platinum cases) was assessed. Logistic regression analyses measured the association between hospital characteristics (region, teaching status, bed size, urban/rural) and satisfactory documentation. TKA/THA implant documentation performance was compared to documentation for endovascular stent procedures. Individual hospitals tended to have very complete (Platinum) or very incomplete (Poor) documentation for both TKA and THA. TKA and THA documentation performance were correlated (correlation coefficient = .70). Teaching hospitals were less likely to have satisfactory documentation for both TKA (P = .002) and THA (P = .029). Documentation for endovascular stent procedures was superior compared to TKA/THA. Hospitals' TKA and THA-related implant documentation performance is generally either very proficient or very poor, in contrast with often well-documented endovascular stent procedures. Hospital characteristics, other than teaching status, do not appear to impact TKA/THA documentation completeness.

15.
Nat Commun ; 14(1): 3449, 2023 06 10.
Artículo en Inglés | MEDLINE | ID: mdl-37301943

RESUMEN

Muscle strength is highly heritable and predictive for multiple adverse health outcomes including mortality. Here, we present a rare protein-coding variant association study in 340,319 individuals for hand grip strength, a proxy measure of muscle strength. We show that the exome-wide burden of rare protein-truncating and damaging missense variants is associated with a reduction in hand grip strength. We identify six significant hand grip strength genes, KDM5B, OBSCN, GIGYF1, TTN, RB1CC1, and EIF3J. In the example of the titin (TTN) locus we demonstrate a convergence of rare with common variant association signals and uncover genetic relationships between reduced hand grip strength and disease. Finally, we identify shared mechanisms between brain and muscle function and uncover additive effects between rare and common genetic variation on muscle strength.


Asunto(s)
Fuerza de la Mano , Enfermedades Musculares , Humanos , Fuerza Muscular/genética , Mutación Missense , Predisposición Genética a la Enfermedad , Proteínas Portadoras
16.
Nat Genet ; 55(6): 927-938, 2023 06.
Artículo en Inglés | MEDLINE | ID: mdl-37231097

RESUMEN

Compelling evidence suggests that human cognitive function is strongly influenced by genetics. Here, we conduct a large-scale exome study to examine whether rare protein-coding variants impact cognitive function in the adult population (n = 485,930). We identify eight genes (ADGRB2, KDM5B, GIGYF1, ANKRD12, SLC8A1, RC3H2, CACNA1A and BCAS3) that are associated with adult cognitive function through rare coding variants with large effects. Rare genetic architecture for cognitive function partially overlaps with that of neurodevelopmental disorders. In the case of KDM5B we show how the genetic dosage of one of these genes may determine the variability of cognitive, behavioral and molecular traits in mice and humans. We further provide evidence that rare and common variants overlap in association signals and contribute additively to cognitive function. Our study introduces the relevance of rare coding variants for cognitive function and unveils high-impact monogenic contributions to how cognitive function is distributed in the normal adult population.


Asunto(s)
Variación Genética , Trastornos del Neurodesarrollo , Humanos , Adulto , Animales , Ratones , Predisposición Genética a la Enfermedad , Fenotipo , Cognición , Proteínas Portadoras/genética , Proteínas Nucleares/genética
17.
PLoS Pathog ; 6(6): e1000925, 2010 Jun 03.
Artículo en Inglés | MEDLINE | ID: mdl-20532212

RESUMEN

The HIV-1 viral infectivity factor (Vif) protein recruits an E3 ubiquitin ligase complex, comprising the cellular proteins elongin B and C (EloBC), cullin 5 (Cul5) and RING-box 2 (Rbx2), to the anti-viral proteins APOBEC3G (A3G) and APOBEC3F (A3F) and induces their polyubiquitination and proteasomal degradation. In this study, we used purified proteins and direct in vitro binding assays, isothermal titration calorimetry and NMR spectroscopy to describe the molecular mechanism for assembly of the Vif-EloBC ternary complex. We demonstrate that Vif binds to EloBC in two locations, and that both interactions induce structural changes in the SOCS box of Vif as well as EloBC. In particular, in addition to the previously established binding of Vif's BC box to EloC, we report a novel interaction between the conserved Pro-Pro-Leu-Pro motif of Vif and the C-terminal domain of EloB. Using cell-based assays, we further show that this interaction is necessary for the formation of a functional ligase complex, thus establishing a role of this motif. We conclude that HIV-1 Vif engages EloBC via an induced-folding mechanism that does not require additional co-factors, and speculate that these features distinguish Vif from other EloBC specificity factors such as cellular SOCS proteins, and may enhance the prospects of obtaining therapeutic inhibitors of Vif function.


Asunto(s)
Proteínas Cullin/metabolismo , VIH-1/metabolismo , Pliegue de Proteína , Proteínas Supresoras de la Señalización de Citocinas/metabolismo , Factores de Transcripción/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Productos del Gen vif del Virus de la Inmunodeficiencia Humana/metabolismo , Secuencia de Aminoácidos , Proteínas Cullin/química , Elonguina , Infecciones por VIH/metabolismo , Infecciones por VIH/patología , Humanos , Inmunoprecipitación , Espectroscopía de Resonancia Magnética , Datos de Secuencia Molecular , Proteínas Supresoras de la Señalización de Citocinas/química , Factores de Transcripción/química , Ubiquitinación , Productos del Gen vif del Virus de la Inmunodeficiencia Humana/química
18.
Eur J Appl Physiol ; 112(3): 1107-16, 2012 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-21748368

RESUMEN

This study investigated the influence of consuming a 2, 6, and 10% carbohydrate-electrolyte (CHO-E) solution on the intermittent endurance capacity and sprint performance of adolescent team games players. Seven participants (five males and two females; mean age 13.3 ± 0.5 years, height 1.71 ± 0.05 m, body mass (BM) 62.0 ± 6.3 kg) performed three trials separated by 3-7 days. In each trial, they completed four 15-min periods of part A of the Loughborough Intermittent Shuttle Test (LIST) followed by an intermittent run to exhaustion (part B). Participants consumed 5 ml kg(-1) BM of the solution during the 5-min pre-exercise period, and a further 2 ml kg(-1) BM every 15 min during part A of the LIST. Intermittent endurance capacity increased by 34% with ingestion of the 6% CHO-E solution compared with the 10% solution (5.5 ± 0.8 vs. 4.1 ± 1.5 min, P < 0.05), equating to a distance of 931 ± 172 versus 706 ± 272 m (P < 0.05). There was no significant difference between the 2% (4.8 ± 1.2 min) and 6% (P = 0.10) or the 2 and 10% solutions (P = 0.09). Carbohydrate concentration did not significantly influence mean 15-m sprint time (P = 0.38). These results suggest that the carbohydrate concentration of an ingested solution influences the intermittent endurance capacity of adolescent team games players with a 6% solution significantly more effective than a 10% solution.


Asunto(s)
Bebidas , Carbohidratos de la Dieta/farmacología , Resistencia Física/efectos de los fármacos , Juego e Implementos de Juego , Carrera , Adolescente , Bebidas/análisis , Niño , Carbohidratos de la Dieta/administración & dosificación , Carbohidratos de la Dieta/análisis , Método Doble Ciego , Femenino , Humanos , Masculino , Concentración Osmolar , Periodicidad , Resistencia Física/fisiología , Carrera/fisiología , Fútbol/fisiología , Factores de Tiempo
19.
Eur J Appl Physiol ; 112(3): 1133-41, 2012 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-21750974

RESUMEN

The aim of this study was to investigate the influence of ingesting a carbohydrate (CHO) gel on the intermittent endurance capacity and sprint performance of adolescent team games players. Eleven participants [mean age 13.5 ± 0.7 years, height 1.72 ± 0.08 m, body mass (BM) 62.1 ± 9.4 kg] performed two trials separated by 3-7 days. In each trial, they completed four 15 min periods of part A of the Loughborough Intermittent Shuttle Test (LIST), followed by an intermittent run to exhaustion (part B). In the 5 min pre-exercise, participants consumed 0.818 mL kg(-1) BM of a CHO or a non-CHO placebo gel, and a further 0.327 mL kg(-1) BM every 15 min during part A of the LIST (38.0 ± 5.5 g CHO h(-1) in the CHO trial). Intermittent endurance capacity was increased by 21.1% during part B when the CHO gel was ingested (4.6 ± 2.0 vs. 3.8 ± 2.4 min, P < 0.05, r = 0.67), with distance covered in part B significantly greater in the CHO trial (787 ± 319 vs. 669 ± 424 m, P < 0.05, r = 0.57). Gel ingestion did not significantly influence mean 15 m sprint time (P = 0.34), peak sprint time (P = 0.81), or heart rate (P = 0.66). Ingestion of a CHO gel significantly increases the intermittent endurance capacity of adolescent team games players during a simulated team games protocol.


Asunto(s)
Rendimiento Atlético , Carbohidratos de la Dieta/farmacología , Resistencia Física/efectos de los fármacos , Juego e Implementos de Juego , Carrera , Aceleración , Adolescente , Rendimiento Atlético/fisiología , Niño , Simulación por Computador , Carbohidratos de la Dieta/administración & dosificación , Método Doble Ciego , Ingestión de Alimentos/efectos de los fármacos , Ingestión de Alimentos/fisiología , Femenino , Fútbol Americano/fisiología , Geles , Hockey/fisiología , Humanos , Masculino , Periodicidad , Resistencia Física/fisiología , Carrera/fisiología , Fútbol/fisiología
20.
J Strength Cond Res ; 25(6): 1592-7, 2011 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-21358422

RESUMEN

Whole-body vibration (WBV) has been shown to elicit acute and chronic improvements in neuromuscular function; however, there is little conclusive evidence regarding an optimum protocol for acute WBV. The aim of this study was to compare the effects of acute exposure to different frequencies of WBV on countermovement jump (CMJ) height. Twelve recreationally trained men (age, 31 ± 8 years; height, 177 ± 12 cm; weight, 83.0 ± 6.9 kg) completed maximal CMJs pre- and post-WBV in a half-squat position for 30 seconds. In a blinded design with randomized testing order, participants were exposed on different days to frequencies of 0, 30, 35, and 40 Hz. Significant main effects were found for time (pre-to-post WBV, p < 0.01) and frequency * time interaction (p < 0.01), with post hoc analysis highlighting that there was a significant mean improvement of 6% in CMJ as a result of WBV at 40 Hz but no significant change at other frequencies. This study demonstrates that for recreationally trained men, an acute 30-second bout of vertical WBV at 40 Hz and 8-mm peak-to-peak displacement significantly enhances explosive jumping performance in comparison to other frequencies. Acute vertical WBV for 30 seconds at 40 Hz may be incorporated into strength and conditioning training to enhance explosive power; however, the exact mechanisms for improvements remain to be elucidated and further well-controlled investigations on chronic WBV training and using well-trained athletes are recommended.


Asunto(s)
Rendimiento Atlético , Vibración , Adulto , Atletas , Humanos , Masculino , Movimiento/fisiología , Fuerza Muscular/fisiología , Músculo Esquelético/fisiología , Adulto Joven
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